Substituents methoxy

Substitution of penicillins by 6a-methoxy was found to be compatible with an a-acidic side chain in terms of antibacterial activity, but less beneficial when the side chain contained an a-acyl or a-ureido substituent. However, analogues of the ureido penicillin VX-VC-43 (Table 2) containing a 6a-methoxy substituent (10) were found to combine good stabiUty to P-lactamase and relatively high antibacterial activity (37). Following an extensive program to identify other 6a-substituents that would stabilize the acyl and ureido series of penicillins, the 6a-formamido series (11) represented by formidacillin (BRL 36650) (Table 2) was developed (38). 

Attempts have also been made to reduce the odor associated with the peracid in the home laundry. Use of a precursor that generates the peracid of a fatty acid can result in an objectionable odor in the wash bath (106). This odor is exacerbated by the higher piC of the peracid versus its parent acid resulting in a greater proportion of the peracid in the unionized and therefore less water-soluble form. To mitigate this circumstance, functionalization of the fatty tail typically alpha to the carbonyl has been utilized (112). The modifications include alpha-chloro and alpha-methoxy substituents on the parent acid portion of the precursor ester. 

These were originally prepared by Khorana as selective protective groups for the 5 -OH of nucleosides and nucleotides. They were designed to be more acid-labile than the trityl group because depurination is often a problem in the acid-catalyzed removal of the trityl group. Introduction of p-methoxy groups increases the rate of hydrolysis by about one order of magnitude for each p-methoxy substituent. For 5 -protected uridine derivatives in 80% AcOH, 20°, the time for hydrolysis was... 

Fig. 10.2. MO diagram for anisole by applicatbn of perturbation for a methoxy substituent.

Using the same methodology, a number of 3,6-dinitro-l,8-naphthyridines (87a-87g) were converted with the LMA/PP system into the methylamino products (94). Tire methylamino group usually enters at position 4, but in cases where a chloro or methoxy substituent is present at C-2, 2,4-bis(methylamino) derivatives were isolated (97MI3). 

R = Ar) and cyclized tricyclic compound 240 (R = Ar) was obtained when 2-bromoacetophenones were reacted with 8-hydroxyquinolin-2(l//)-one under the above conditions. Presence of a 4-methoxy substituent shifted the equilibrium to the ring-opened product 241 (R = 4-MeOPh), while that of 4-nitro group gave only cyclized product 240 (R = N02). Similarly, mixtures of ring-opened and 2,3,6,7-tetrahydro-5//-pyrido[l,2,3- /e]-l,4-benzoxazin-5-one derivatives were formed in the reaction of 8-hydroxy-l,2,3,4-tetrahydroquinolin-2-one and halomethyl ketones (00HCA349). 

Azido-3-methoxypyridazines 1 are transformed into 6,7-dimethoxy-477-1,2.5-triazepines 3 by irradiation in the presence of sodium methoxide. The reaction proceeds via the unstable 277-tautomers 2, which were detected by NMR spectroscopy and can be trapped as the 2-acetyl derivatives 4 by adding acetyl chloride to the crude photolysate.371 The synthesis fails for azidopyridazines lacking the 3-methoxy substituent. 

Interestingly, when R1 and R2 are hydrogens, the -configurated amino nitriles 1 arc obtained, whereas one or two methoxy substituents on the aromatic ring leads to (S)-diastereomers. This surprising effect is caused by the preferential crystallization of the (R)- or the (.S )-diastereomers, respectively. If the pure diastereomers of 1 are dissolved in methanol, equilibration occurs. On concentration, the optically pure diastereomer again crystallizes from the solution45. 

Several authors studied the influence of substituents on activation parameters. Bad-dar et al.315 who studied the polyesterification of y-arylitaconic anhydrides and adds with 1,2-ethanediol found that in the non-catalyzed reaction a p-methoxy substituent decreases both the activation enthalpy and the entropy whereas an increase is observed with a p-chloro substituent. On the other hand, Huang et al., who studied the esterification of 2,2-dimethyl-l,3-propanediol with benzoic, butanedioic, hexanedioic, decanedioic and o-phthalic add found the same values since the activation enthalpy is 64 kJ mol-1 for the first reaction and 61 kJ mol-1 for the others. 

Recently, a kinetic study has been made of the substitution of diazotised sulphanilic acid in the 2 position of 4-substituted phenols under first-order conditions (phenol in excess) in aqueous buffer solutions at 0 °C131a. A rough Hammett correlation existed between reaction rates and am values, with p about -3.8 however, the point for the methoxy substituent deviated by two orders of magnitude and no explanation was available for this. The unexpectedly low p-factor was attributed to the high reactivities of the aromatic substrates, so that the transition state would be nearer to the ground state than for reaction of monosubstituted benzene derivatives. 

The effects of some methoxy substituents were determined for the reaction with diphenylmethanol at a range of sulphuric acid concentrations in acetic acid containing 0.55 M water at 25 °C (Table 92)366. The logarithms of the rate coeffi-... 

Gore et al.426 have used chloroform as a solvent for acetylation catalysed by aluminium chloride and at 45-55 °C find that a 2-methoxy substituent in naphthalene increases the reactivity of the 1 position 1.72 times, of the 6 position 3.8 times, and of the 8 position, 0.9 times the former and latter of these results indicate a considerable steric effect. Likewise, a 2-bromo substituent caused the reactivity of the 6 and 8 positions to be 0.63 and 0.58 times that of the corresponding positions in the unsubstituted compound. At 20-25 °C the relative reactivities of some polycyclics were as follows427 1-naphthyl, 1.0 3-phenanthryl 0.64 9-phenanthryl, 0.02 1-phenanthryl, 0.29 2-naphthyl, 0.28 2-phenanthryl, 0.12 4-phenanthryl, 0.0085. Some of these results seem to be due to steric hindrance, and the large difference in reactivity of naphthalene and biphenyl seems erroneous. 

Concerning the arylbromide, the para-substituents Y play an important role as expected and as shown in the table (Fig. 13) for the arylation of 1-butanol, the electron donating substituent lowers the yield but only to 90 % for the methoxy substituent on the contrary the hydroxy substituent inhibits fully the arylation owing probably to the much higher electron donating character of this group in the basic conditions used. 

An electron donating butadiene with the methoxy substituents at the 1 and 4 positions was calculated to undergo a concerted [4+2] cycloaddition reaction with TCNE as... 

The relative rates of cycloaddition of 88b-88e were measured in comparison with that of the parent 88a as a reference. The methoxy substituent has practically no effect on the reaction rate. However, it is apparent that electron-withdrawing substituents (88b, 88c and 88e) significantly accelerate the anti-addition, whereas in xyn-addition the acceleration is not as large the rate is comparable to that of the reference compound (88a). In the reactions of the tetrafluoro-substituted dienophile 88d, we found significant rate acceleration on both sides, though anti-side addition was still substantially favored. 

Substituted pyrimidine N-oxides such as 891 are converted analogously into their corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 afford the 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6). The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme 7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines 900 are formed nearly exclusively, combination of a 4-methoxy substituent with a 5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive formation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimidine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formed by reaction of the amino group in 902 with DMF in the presence of TCS 14 [23] (Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides react with 18 under a variety of conditions, e.g. in the presence of ZnBr2 [22]. 

White and Deerberg explored this reaction system in connection with the synthesis of a portion of the structure of rapamycin.165 Better yields were observed from benzyloxy than for a methoxy substituent, and there was a slight enhancement of stereoselectivity with the addition of ERG substituents to the benzyloxy group. 

Benzyl groups having 4-methoxy (PMB) or 3,5-dimethoxy (DMB) substituents can be removed oxidatively by dichlorodicyanoquinone (DDQ).181 These reactions presumably proceed through a benzylic cation and the methoxy substituent is necessary to facilitate the oxidation. 

A-methoxy-A-methyl amides.87 LiAlH4 and DiBAlH have both been used as the hydride donor. The partial reduction is again the result of the stability of the initial reduction product. The A-methoxy substituent leads to a chelated structure that is stable until acid hydrolysis occurs during workup. 

Imidate esters can also be generated by reaction of imidoyl chlorides and allylic alcohols. The lithium anions of these imidates, prepared using lithium diethylamide, rearrange at around 0°C. When a chiral amine is used, this reaction can give rise to enantioselective formation of 7, 8-unsaturated amides. Good results were obtained with a chiral binaphthylamine.265 The methoxy substituent is believed to play a role as a Li+ ligand in the reactive enolate. 

V-Methyl-A-methoxyamides are also useful starting materials for preparation of ketones Again, the reaction depends upon the stability of the tetrahedral intermediate against elimination and a second addition step. In this case chelation with the IV-methoxy substituent is responsible. 

Arg217 located in the S4-S5 subsites but this did not occur. The electron-donating methoxy substituent was introduced to enhance the departure of the benzylic leaving group X. But there was no enhancement.35... 

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